Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration.
Journal
Nature cardiovascular research
ISSN: 2731-0590
Titre abrégé: Nat Cardiovasc Res
Pays: England
ID NLM: 9918284280206676
Informations de publication
Date de publication:
Jul 2022
Jul 2022
Historique:
received:
23
04
2021
accepted:
24
05
2022
medline:
1
7
2022
pubmed:
1
7
2022
entrez:
28
8
2024
Statut:
ppublish
Résumé
In mammals, the physiological activation of the glucocorticoid receptor (GR) by glucocorticoids (GCs) promotes the maturation of cardiomyocytes during late gestation, but the effect on postnatal cardiac growth and regenerative plasticity is unclear. Here we demonstrate that the GC-GR axis restrains cardiomyocyte proliferation during postnatal development. Cardiomyocyte-specific GR ablation in conditional knockout (cKO) mice delayed the postnatal cardiomyocyte cell cycle exit, hypertrophic growth and cytoarchitectural maturation. GR-cKO hearts showed increased expression of genes involved in glucose catabolism and reduced expression of genes promoting fatty acid oxidation and mitochondrial respiration. Accordingly, oxygen consumption in GR-cKO cardiomyocytes was less dependent on fatty acid oxidation, and glycolysis inhibition reverted GR-cKO effects on cardiomyocyte proliferation. GR ablation or transient pharmacological inhibition after myocardial infarction in juvenile and/or adult mice facilitated cardiomyocyte survival, cell cycle re-entry and division, leading to cardiac muscle regeneration along with reduced scar formation. Thus, GR restrains heart regeneration and may represent a therapeutic target.
Identifiants
pubmed: 39196236
doi: 10.1038/s44161-022-00090-0
pii: 10.1038/s44161-022-00090-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
617-633Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Bongiovanni, C. et al. Reawakening the intrinsic cardiac regenerative potential: molecular strategies to boost dedifferentiation and proliferation of endogenous cardiomyocytes. Front. Cardiovasc. Med. 8, 750604 (2021).
pubmed: 34692797
pmcid: 8531484
doi: 10.3389/fcvm.2021.750604
Tzahor, E. & Poss, K. D. Cardiac regeneration strategies: staying young at heart. Science 356, 1035–1039 (2017).
pubmed: 28596337
pmcid: 5614484
doi: 10.1126/science.aam5894
Sadek, H. & Olson, E. N. Toward the goal of human heart regeneration. Cell Stem Cell 26, 7–16 (2020).
pubmed: 31901252
pmcid: 7257208
doi: 10.1016/j.stem.2019.12.004
Eschenhagen, T. et al. Cardiomyocyte regeneration: a consensus statement. Circulation 136, 680–686 (2017).
pubmed: 28684531
pmcid: 5557671
doi: 10.1161/CIRCULATIONAHA.117.029343
van Berlo, J. H. & Molkentin, J. D. An emerging consensus on cardiac regeneration. Nat. Med. 20, 1386–1393 (2014).
pubmed: 25473919
pmcid: 4418535
doi: 10.1038/nm.3764
Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011).
pubmed: 21350179
pmcid: 3099478
doi: 10.1126/science.1200708
Drenckhahn, J.-D. et al. Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development. Dev. Cell 15, 521–533 (2008).
pubmed: 18854137
doi: 10.1016/j.devcel.2008.09.005
Sampaio-Pinto, V. et al. Neonatal apex resection triggers cardiomyocyte proliferation, neovascularization and functional recovery despite local fibrosis. Stem Cell Rep. 10, 860–874 (2018).
doi: 10.1016/j.stemcr.2018.01.042
Haubner, B. J. et al. Complete cardiac regeneration in a mouse model of myocardial infarction. Aging 4, 966–977 (2012).
pubmed: 23425860
pmcid: 3615162
doi: 10.18632/aging.100526
Ye, L. et al. Early regenerative capacity in the porcine heart. Circulation 138, 2798–2808 (2018).
pubmed: 30030417
doi: 10.1161/CIRCULATIONAHA.117.031542
Zhu, W. et al. Regenerative potential of neonatal porcine hearts. Circulation 138, 2809–2816 (2018).
pubmed: 30030418
pmcid: 6301098
doi: 10.1161/CIRCULATIONAHA.118.034886
Li, Y. et al. Genetic tracing identifies early segregation of the cardiomyocyte and nonmyocyte lineages. Circ. Res. 125, 343–355 (2019).
pubmed: 31185811
doi: 10.1161/CIRCRESAHA.119.315280
Jopling, C. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010).
pubmed: 20336145
pmcid: 2846535
doi: 10.1038/nature08899
Kikuchi, K. et al. Primary contribution to zebrafish heart regeneration by gata4
pubmed: 20336144
pmcid: 3040215
doi: 10.1038/nature08804
Soonpaa, M. H., Kim, K. K., Pajak, L., Franklin, M. & Field, L. J. Cardiomyocyte DNA synthesis and binucleation during murine development. Am. J. Physiol. 271, H2183–H2189 (1996).
pubmed: 8945939
Li, F., Wang, X., Capasso, J. M. & Gerdes, A. M. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J. Mol. Cell. Cardiol. 28, 1737–1746 (1996).
pubmed: 8877783
doi: 10.1006/jmcc.1996.0163
Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).
pubmed: 19342590
pmcid: 2991140
doi: 10.1126/science.1164680
Senyo, S. E. et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493, 433–436 (2013).
pubmed: 23222518
doi: 10.1038/nature11682
Uygur, A. & Lee, R. T. Mechanisms of cardiac regeneration. Dev. Cell 36, 362–374 (2016).
pubmed: 26906733
pmcid: 4768311
doi: 10.1016/j.devcel.2016.01.018
Heallen, T. R., Kadow, Z. A., Kim, J. H., Wang, J. & Martin, J. F. Stimulating cardiogenesis as a treatment for heart failure. Circ. Res. 124, 1647–1657 (2019).
pubmed: 31120819
pmcid: 6534162
doi: 10.1161/CIRCRESAHA.118.313573
Hashimoto, H., Olson, E. N. & Bassel-Duby, R. Therapeutic approaches for cardiac regeneration and repair. Nat. Rev. Cardiol. 15, 585–600 (2018).
pubmed: 29872165
pmcid: 6241533
doi: 10.1038/s41569-018-0036-6
Cahill, T. J., Choudhury, R. P. & Riley, P. R. Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Nat. Rev. Drug Discov. 16, 699–717 (2017).
pubmed: 28729726
doi: 10.1038/nrd.2017.106
Galdos, F. X. et al. Cardiac regeneration: lessons from development. Circ. Res. 120, 941–959 (2017).
pubmed: 28302741
pmcid: 5358810
doi: 10.1161/CIRCRESAHA.116.309040
Oakley, R. H. & Cidlowski, J. A. Glucocorticoid signaling in the heart: a cardiomyocyte perspective. J. Steroid Biochem. Mol. Biol. 153, 27–34 (2015).
pubmed: 25804222
pmcid: 4568128
doi: 10.1016/j.jsbmb.2015.03.009
Richardson, R. V., Batchen, E. J., Denvir, M. A., Gray, G. A. & Chapman, K. E. Cardiac GR and MR: from development to pathology. Trends Endocrinol. Metab. 27, 35–43 (2016).
pubmed: 26586027
doi: 10.1016/j.tem.2015.10.001
Rog-Zielinska, E. A., Richardson, R. V., Denvir, M. A. & Chapman, K. E. Glucocorticoids and foetal heart maturation; implications for prematurity and foetal programming. J. Mol. Endocrinol. 52, R125–R135 (2014).
pubmed: 24299741
doi: 10.1530/JME-13-0204
Giraud, G. D., Louey, S., Jonker, S., Schultz, J. & Thornburg, K. L. Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus. Endocrinology 147, 3643–3649 (2006).
pubmed: 16690807
doi: 10.1210/en.2006-0061
Feng, X., Reini, S. A., Richards, E., Wood, C. E. & Keller-Wood, M. Cortisol stimulates proliferation and apoptosis in the late gestation fetal heart: differential effects of mineralocorticoid and glucocorticoid receptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R343–R350 (2013).
pubmed: 23785077
pmcid: 3833392
doi: 10.1152/ajpregu.00112.2013
de Vries, W. B. et al. Suppression of physiological cardiomyocyte proliferation in the rat pup after neonatal glucocorticosteroid treatment. Basic Res. Cardiol. 101, 36–42 (2006).
pubmed: 16283594
doi: 10.1007/s00395-005-0557-0
Gay, M. S., Li, Y., Xiong, F., Lin, T. & Zhang, L. Dexamethasone treatment of newborn rats decreases cardiomyocyte endowment in the developing heart through epigenetic modifications. PLoS ONE 10, e0125033 (2015).
pubmed: 25923220
pmcid: 4414482
doi: 10.1371/journal.pone.0125033
Cutie, S., Payumo, A. Y., Lunn, D. & Huang, G. N. In vitro and in vivo roles of glucocorticoid and vitamin D receptors in the control of neonatal cardiomyocyte proliferative potential. J. Mol. Cell. Cardiol. 142, 126–134 (2020).
pubmed: 32289320
pmcid: 7395852
doi: 10.1016/j.yjmcc.2020.04.013
Tao, Z. et al. Dexamethasone inhibits regeneration and causes ventricular aneurysm in the neonatal porcine heart after myocardial infarction. J. Mol. Cell. Cardiol. 144, 15–23 (2020).
pubmed: 32387242
doi: 10.1016/j.yjmcc.2020.04.033
Hattori, F. et al. Nongenetic method for purifying stem cell-derived cardiomyocytes. Nat. Methods 7, 61–66 (2010).
pubmed: 19946277
doi: 10.1038/nmeth.1403
Genangeli, M. et al. Development and application of a UHPLC–MS/MS method for the simultaneous determination of 17 steroidal hormones in equine serum. J. Mass Spectrom. 52, 22–29 (2017).
pubmed: 27790795
doi: 10.1002/jms.3896
Morgan, R. A. et al. Dysregulation of cortisol metabolism in equine pituitary pars intermedia dysfunction. Endocrinology 159, 3791–3800 (2018).
pubmed: 30289445
pmcid: 6202856
doi: 10.1210/en.2018-00726
Perogamvros, I., Ray, D. W. & Trainer, P. J. Regulation of cortisol bioavailability—effects on hormone measurement and action. Nat. Rev. Endocrinol. 8, 717–727 (2012).
pubmed: 22890008
doi: 10.1038/nrendo.2012.134
Savu, L., Nunez, E. & Jayle, M. F. Corticosterone binding by mouse sera during foetal and post-natal development. Acta Endocrinol. 84, 177–190 (1977).
doi: 10.1530/acta.0.0840177
Oakley, R. H. et al. Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease. Proc. Natl Acad. Sci. USA 110, 17035–17040 (2013).
pubmed: 24082121
pmcid: 3801058
doi: 10.1073/pnas.1302546110
Ali, H., Braga, L. & Giacca, M. Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture. FEBS J. 287, 417–438 (2020).
pubmed: 31743572
doi: 10.1111/febs.15146
Piquereau, J. & Ventura-Clapier, R. Maturation of cardiac energy metabolism during perinatal development. Front. Physiol. 9, 959 (2018).
pubmed: 30072919
pmcid: 6060230
doi: 10.3389/fphys.2018.00959
Bae, J., Paltzer, W. G. & Mahmoud, A. I. The role of metabolism in heart failure and regeneration. Front. Cardiovasc. Med. 8, 702920 (2021).
pubmed: 34336958
pmcid: 8322239
doi: 10.3389/fcvm.2021.702920
Sim, C. B. et al. Sex-specific control of human heart maturation by the progesterone receptor. Circulation 143, 1614–1628 (2021).
pubmed: 33682422
pmcid: 8055196
doi: 10.1161/CIRCULATIONAHA.120.051921
Kubin, T. et al. Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling. Cell Stem Cell 9, 420–432 (2011).
pubmed: 22056139
doi: 10.1016/j.stem.2011.08.013
D’Uva, G. et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat. Cell Biol. 17, 627–638 (2015).
pubmed: 25848746
doi: 10.1038/ncb3149
Puente, B. N. et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157, 565–579 (2014).
pubmed: 24766806
pmcid: 4104514
doi: 10.1016/j.cell.2014.03.032
Honkoop, H. et al. Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart. eLife 8, e50163 (2019).
pubmed: 31868166
pmcid: 7000220
doi: 10.7554/eLife.50163
Cardoso, A. C. et al. Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression. Nat. Metab. 2, 167–178 (2020).
pubmed: 32617517
pmcid: 7331943
doi: 10.1038/s42255-020-0169-x
Mills, R. J. et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc. Natl Acad. Sci. USA 114, E8372–E8381 (2017).
pubmed: 28916735
pmcid: 5635889
doi: 10.1073/pnas.1707316114
Cao, T. et al. Fatty acid oxidation promotes cardiomyocyte proliferation rate but does not change cardiomyocyte number in infant mice. Front. Cell Dev. Biol. 7, 42 (2019).
pubmed: 30968022
pmcid: 6440456
doi: 10.3389/fcell.2019.00042
Severinova, E. et al. Glucocorticoid receptor-binding and transcriptome signature in cardiomyocytes. J. Am. Heart Assoc. 8, e011484 (2019).
Talman, V. et al. Molecular atlas of postnatal mouse heart development. J. Am. Heart Assoc. 7, e010378 (2018).
pubmed: 30371266
pmcid: 6474944
doi: 10.1161/JAHA.118.010378
Parikh, S. S. et al. Thyroid and glucocorticoid hormones promote functional T-tubule development in human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res. 121, 1323–1330 (2017).
pubmed: 28974554
pmcid: 5722667
doi: 10.1161/CIRCRESAHA.117.311920
Karbassi, E. et al. Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine. Nat. Rev. Cardiol. 17, 341–359 (2020).
pubmed: 32015528
pmcid: 7239749
doi: 10.1038/s41569-019-0331-x
Hirose, K. et al. Evidence for hormonal control of heart regenerative capacity during endothermy acquisition. Science 364, 184–188 (2019).
pubmed: 30846611
pmcid: 6541389
doi: 10.1126/science.aar2038
Su, Q.-Q., Huang, X.-L., Qin, J. & Liu, Q.-S. Assessment of effects of mifepristone administration to lactating mice on the development and fertility of their progeny. J. Obstet. Gynaecol. Res. 41, 575–581 (2015).
pubmed: 25331362
doi: 10.1111/jog.12589